The invention pertains to cyclohexylamine derivatives as N-Methyl-D-Aspartate Antagonists (NMDA).
Over excitation of NMDA receptor channel complexes on postsynaptic neurons following excessive release of glutamic acid from synaptosomes and glutamic acid from synaptosomes and glial cells result in a massive calcium ion influx into the neuronal cells, which leads to their death. This is believed to occur under ischemic or hypoxic conditions such as stroke, hypoglycemic, cardiac arrest and physical trauma. An NMDA receptor antagonist might be therapeutically useful because it may minimize damage of the central nervous system (CNS) induced by ischemic or hypoxic conditions. The NMDA receptor channel complex consists of at least three binding domains including glutamic acid (or NMDA) recognition site, channel blocking binding site, and strychnine-insensitive glycine binding type. Physiologically, a blockade of at least one of these sites terminates the channel opening of the NMDA receptor to prevent a calcium ion influx (Nagata R. et al., J. Med. Chem., 1994;37:3956-3968).
Excessive excitation by neurotransmitters may be responsible for the loss of neurons in cerebral vascular disorders such as cerebral ischemia or cerebral infauxtion resulting in a range of conditions such as thromboembolic or hemorrhagic stroke, cerebral vasospasm, hypoglycemia, cardiac arrest, status epilepticus, perinatal, asphyxia anoxia, such as from near drowning, pulmonary surgery and cerebral trauma, as well as lathyrism, Alzheimer""s disease, and Huntington""s disease. Such conditions likewise suggest the use of agents that may act as antagonists in the receptors identified above may lead to treatment of amyotrophic lateral sclerosis (ALS), schizophrenia, parkinsonism, epilepsy, anxiety, pain, and drug addiction (PCT/EPO 94/01492 having publication number WO 94/26747 published Nov. 24, 1994, Watjen et al.).
L-glutamic acid, L-aspartic acid, and a number of other closely related amino acids have the ability to activate neurons in the nervous system and therefor the vast majority of excitatory neurons in the mammalian CNS. Interaction with glutamic acid mediated neurotransmission is considered a useful approach in the treatment of neurological and psychiatric diseases (WO 94/26746, published Nov. 24, 1994, Jacobsen et al.).
Excitatory amino acid receptor antagonists that block NMDA receptors are recognized for usefulness in the treatment of a variety of disorders. NMDA receptors are intimately involved in the phenomenon of excitotoxicity, which may be a critical determinant of outcome of several neurological disorders. Disorders known to be responsive to blockade of the NMDA receptor include acute cerebral ischemia (stroke or cerebral trauma, for example), muscular spasm, convulsive disorders, neuropathic pain and anxiety, and may be a significant causal factor in chronic neurodegenerative disorders such as Parkinson""s disease (Klockgether T., Turski L., Ann. Neurol., 1993;34:585-593); human immunodeficiency virus (HIV) related neuronal injury, amyotrophic laterial sclerosis (ALS), Alzheimer""s disease (Francis P. T., Sims N. R., Procter A. W., Bowen D. M., J. Neurochem., 1993;60(5):1589-1604); and Huntington""s disease (see Lipton S., TINS, 1933;16(12):527-532; Lipton V, Rosenberg P. A., New Eng. J. Med., 1994;330(9):613-622; and Bigge C. F., Biochem. Pharmacol., 1993;45:1547-1561, and references cited therein). NMDA receptor antagonists may also be used to prevent tolerance to opiate analgesia or to help control withdrawal symptoms from addictive drugs (European Patent Application 488,959A).
Many of the properties of native NMDA receptors are seen in recombinant homomeric NR1 receptors. These properties are altered by the NR2 subunits. Recombinant NMDA receptors expressed in Xenopus Oocytes have been studied by voltage-clamp recording, and has developmental and regional expression of the mRNAs encoding NMDA receptor subunits. Electrophysiological assays were utilized to characterize the actions of compounds at NMDA receptors expressed in Xenopus Oocytes. The compounds were assayed at four subunit combinations at cloned rat NMDA receptors, corresponding to three putative NMDA receptor subtypes (Moriyoshi et al., Nature, 1991;354:31-37; Monyer et al., Science, 1992; 256:1217-1221; Kutsuwada et al, Nature, 1992;358:36-41; Sugihara et al., Biochem. Biophys Res. Commun., 1992;185:826-832).
Expression cloning of the first NMDA receptor subunit, NMDAR1 (NR1) in Nakanishi""s lab in 1991 provided an initial view of the molecular structure of the NMDA receptor (Moriyoshi, supra., 1991). There are several other structurally related subunits (NMDAR2A through NMDAR2D) that join NR1 in heteromeric assemblies to form the functional ion channel complex of the receptor (Annu. Rev. Neurosci., 1994; 17:31-108). The molecular heterogeneity of NMDA receptors implies a future potential for agents with subtype selective pharmacology.
Described are cyclohexylamines derivatives of Formula I and their pharmaceutically acceptable salts thereof 
wherein:
Ar is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, which heteroaryl is from 5 to 14 atoms having from 1 to 2 heteroatoms selected from the group consisting of N, O, and S with from 0 to 2 substituents for each; the substituents are from the groups F, Cl, Br, I, CN, NO2, OCH3, OC(O)CH3, CF3, OCH2CH2OH or N(CH3)2; 
or entgegen or zusammen xe2x80x94CH(R1)xe2x95x90CH(R2)xe2x80x94,
E is hydrogen or OH;
d is an integer of from 0 to 2;
n is an integer from 1 to 6;
q is an integer from 0 to 6;
R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, OH, hydroxyalkyl, aminoalkyl, aralkyl, or N(R4)(R5) wherein R4 and R5 are independently selected from hydrogen, alkyl, aralkyl, heteroaryl, heteroaralkyl, aminoalkyl, hydroxyalkyl, and thioalkyl;
R is hydrogen, alkyl, C(O)R6, C(O)OR6, C(O)NHR6, H2NC(O)-alkyl, aralkyl, cycloalkyl (3-7 carbon atoms) alkyl, hydroxyalkyl, aminoalkyl, amino(hydroxy)alkyl, carboxyalkyl, heteroaralkyl, alkenylalkyl, or OH wherein R6 is alkyl or aralkyl;
X is independently selected from hydrogen or an electron withdrawing group;
Y is a hydrogen bond donor group; and
* denotes cis or trans or a mixture thereof.
The invention also relates to compounds of Formula II 
or a pharmaceutically acceptable salt thereof wherein:
Ar is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, which heteroaryl is from 5 to 14 atoms having from 1 to 2 heteroatoms selected from the group consisting of N, O, and S with from 0 to 2 substituents for each; the substituents are from the groups F, Cl, Br, I, CN, NO2, OCH3, OC(O)CH3, CF3, OCH2CH2OH, or N(CH3)2;
E is hydrogen or OH; 
xe2x80x83d is an integer from 0 to 2;
t is an integer from 1 to 3;
R1 and R2 are independently selected from hydrogen, alkyl, OH, hydroxyalkyl, aminoalkyl, thioalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, guanidinyl, (aminocarbonyl)alkyl-, carboxyalkyl-, (methylthio)-alkyl-, or N(R4)(R5) wherein R4 and R5 are independently selected from hydrogen, alkyl, aralkyl, heteroaryl, heteroaralkyl, ureidoalkyl, aminoalkyl, hydroxyalkyl, or thioalkyl;
R3 is hydrogen, alkyl, OH, or aralkyl;
R is hydrogen, alkyl, C(O)R6, C(O)OR6, C(O)NHR6, H2NC(O)-alkyl, aralkyl, hydroxyalkyl, aminoalkyl, amino(hydroxy)alkyl, carboxyalkyl, heteroaralkyl, alkenylalkyl, or OH wherein R6 is alkyl or aralkyl;
X is independently selected from hydrogen or an electron withdrawing group;
Y is a hydrogen bond donor group; and
* denotes cis or trans or a mixture thereof.
The invention is also concerned with a pharmaceutical composition useful for treating disorders responsive to the selective blockade of N-methyl-D-aspartate receptor subtypes in a mammal, including a human, suffering therefrom which comprises a therapeutically effective amount of at least one compound of Formula I, or Formula II or Formula III, and the pharmaceutically acceptable salts thereof. The composition is useful for treating optionally disorders such as stroke, cerebral ischemia, trauma, hypoglycemia, neurodegenerative disorders, anxiety, depression, migraine headache, convulsions, aminoglycoside antibiotic-induced hearing loss, psychosis, glaucoma, CMV retinitis, opioid tolerance or withdrawal, chronic pain, or urinary incontinence.
The invention is also concerned with a method of treating disorders responsive to the selective blockade of the N-methyl-D-aspartate receptor subtypes in a mammal, including a human, suffering therefrom which comprises administering in unit dosage form, at least one compound represented by Formulas I-III or their pharmaceutically acceptable salts thereof.